Synthesis and biological evaluation of a novel sigma-1 receptor antagonist based on 3,4-dihydro-2(1H)-quinolinone scaffold as a potential analgesic

• A series of 3,4-dihydro-2(1H)-quinolinone derivatives were designed and synthesized.
• The targeted compounds were evaluated affinity for sigma-1 and sigma-2 receptors.
• Selected compounds were evaluated the functional profile on sigma-1 receptor.
• In addition, the most active compounds were tested in formalin test.

The synthesis and sigma-1 receptor (σ1R) antagonist activity of a new series of 3,4-dihydro-2(1H)-quinolinone derivatives are reported. The new compounds were evaluated in vitro in sigma-1 and sigma-2 receptor-binding assays in guinea pig brain membranes. The structure–activity relationship led us to the promising derivative 7-(3-(piperidin-1-yl)propoxy)-1-(4-fluorobenzyl)-3,4-dihydro-2(1H)-quinolinone (35). The compounds with highest affinity and greatest selectivity were further profiled, and compound 35 had a high binding constant for sigma-1 receptor (Kiσ1 = 1.22 nM) and high sigma-1/2 selectivity (1066-fold). Thus, compound 35, which proved to be an antagonist of sigma-1 receptor, emerged as the most interesting candidate. In addition, compound 35 exerted dose-dependent anti-nociceptive effects in the formalin test. These characteristics suggested that the potent and selective compound 35 could be a potent candidate for pain treatment.

A series of novel 3,4-dihydro-2(1H)-quinolinone derivatives have been synthesized. The target compounds have been evaluated for anti-nociceptive activity in vitro and vivo.Figure optionsDownload as PowerPoint slide